The foundation for this Project is a body of work now published in Nature Medicine. We developed a refined theory for the development of autoimmunity, the theory of autoantigen complementarity. Its components indicate that autoimmunity is not incited by the autoantigen but by a protein complementary surface structure to the autoantigen, i.e., a protein homologous to or identical to the amino acid sequence of the translated antisense RNA from the autoantigen gene. The complementary protein incites the production of antibodies (Ab1), which elicit an anti-antibody or anti-idiotypic response (Ab2). The anti-idiotypic antibody (Ab2 or autoantibody) now recognizes and reacts with the autoantigen. We have strong evidence that a protein complementary to PR3 incites PR3-ANCA glomerulonephritis and that the autoantibodies (ANCA) are produced as a consequence of the idiotypic network. Our overall objective through this second funding period is to continue research efforts to provide support for and extend this newly developed theory. In specific aim 1, we propose to determine if there are restricted regions of the complementary-proteins that can incite the cascade leading to the production of pathogenic ANCA. As we identify antibodies reactive with varying epitopes, we will determine idiotypic relationships between antibodies reactive with compementary-proteins and ANCA. In this context, we plan to follow patients over time to ascertain whether the anticomplementary-antibody repertoire varies with disease activity and assess how this affects ANCA specificity. Lastly, we will determine if T-cells from ANCA patients respond to the complementary proteins. In specific aim 2, we propose to isolate and identify the source of the complementary proteins, which function as inciting immunogens. One potential source is an invading microbe, and a second is that the individuals are producing it themselves by translating antisense RNA. In specific aim 3 we propose to determine the general nature of the theory of autoantigen complementarity by exploring its components in anti-GBM disease.